Multiple myeloma (MM) is a plasma cell malignancy characterized by cellular resistance to apoptosis leading to prolonged survival and accumulation of tumor cells in the bone marrow microenvironment. Standardized incidence rates of MM are increasing and are typically two-fold higher among African Americans and men. Although the etiology of MM is unclear, it is preceded by precursor asymptomatic plasma cell dyscrasias known as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Despite the availability of clinical risk models, genomic aberrations and imaging, efforts to utilize these indices to accurately classify early stage precursor disease and monitor clinical course have not been successful. Alternatively, recent advances in transcriptome sequencing offer new opportunities to characterize miRNAs as novel biomarkers, which could significantly change the paradigm of MM classification, management and treatment. The goal of the proposed Exploratory/Developmental investigation is to characterize the role of heparanase (HPSE), a potent tumor regulator, and exosome mircroRNAs (miRNA) as biomarkers for early detection, classification and progression of individuals at highest risk for developing MM from asymptomatic precursor states. We will test the overarching hypothesis that serum exosome HPSE and miRNA profiles correlate with myeloma progression. To address this hypothesis we intend to: (1) characterize HPSE protein levels in exosomes isolated from the sera of patients with MGUS, SMM and MM and sex-, age-, ancestry-matched controls; (2) conduct miRNA profiling in serum exosomes; and (3) determine the extent to which HPSE influences exosome miRNA composition relative to myeloma progression. We intend to capitalize on a unique opportunity to explore these relationships in a large, well-characterized population of myeloma, while taking advantage of recent advances in HPSE and exosome biology and genome sequencing. We anticipate that findings from this investigation will be highly informative and provide the foundation necessary to propose biologic mechanisms underlying myelomagenesis as well as new biomarkers for disease. These novel biomarkers could significantly change the paradigm for myeloma diagnosis, classification, management and treatment and improve overall survival by reducing morbidity and mortality associated with advanced stage disease.